Oxidation reaction excellent in conversion rate

ABSTRACT

A process for preparing 3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4,-benzodiazepin-3-yl]propionic acid methyl ester at a high conversion rate with good reproducibility by oxidizing 3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester in the presence of an oxidation catalyst is provided by defining the ammonium ion content of 3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester.

FIELD OF THE INVENTION

The present invention relates to a process for preparing3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester by subjecting, to an oxidation reaction, a compoundselected from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester.

More specifically, the present invention relates to a novel preparationprocess capable of providing3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester at a high conversion rate (reaction efficiency) withgood reproducibility even when an oxidation reaction is conducted using,as a raw material, a compound selected from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester which are each an unpurified compound.

BACKGROUND ART

Each reaction step for preparing an active pharmaceutical ingredientshould be a step that proceeds with a good reaction yield, is conductedwith good reproducibility, can provide a high-purity product, and isthus suited for industrial production. Impurities which have appeared ineach preparation process can be removed in a purification step, but apreparation process having such a purification step is not always aprocess suited for industrial production, because the purification stepmakes the work cumbersome and reduces a working efficiency. Moreover, anincrease in the frequency of the purification step may reduce a totalyield of a desired active pharmaceutical ingredient. There is thereforea demand for the establishment of a preparation process in which thenumber of purification steps is reduced as much as possible and which,as described above, proceeds with a good reaction yield, provides ahigh-purity product with good reproducibility, and is thus suited forindustrial production.

3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2,-a][1,4]benzodiazepin-4-yl]propionicacid methyl ester benzenesulfonate is a compound having sedative andanesthetic actions.

Patent Document 1 that discloses a preparation process of the compounddescribes a process for preparing3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester by subjecting3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]-diazepin-3-yl]propionicacid methyl ester purified by recrystallization to Dess-Martin(Dess-Martin periodinane) oxidation or TEMPO(2,2,6,6-tetramethylpiperidin-N-oxyl) oxidation.

The Dess-Martin oxidation or TEMPO oxidation used in the above processis a well-known process for converting a secondary alcohol compound intoa corresponding ketone compound (Non-patent Documents 1 to 4). AlthoughDess-Martin oxidation is capable of oxidizing a secondary alcoholcompound under mild conditions, it is not completely suited for theindustrial level production, because as is already known, the reagentitself is potentially explosive. On the other hand, it is said thatTEMPO oxidation can be conducted under mild conditions and is anoxidation reaction ordinarily usable in the industrial level production.It has however been pointed out that TEMPO oxidation of an aromaticring-containing compound causes chlorination of the aromatic ring as aside reaction and this problem may lead to a reduction in yield of atarget compound in TEMPO oxidation (refer to Non-patent Document 5).

Thus, there is not known a industrially suited process for preparing3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester which is a synthesis intermediate of3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionicacid methyl ester benzenesulfonate by oxidizing3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, which is a raw material compound of the intendedcompound, safely with a high efficiency.

PRIOR ART DOCUMENT Patent Document

-   [Patent Document 1] WO 2011/032692

Non-Patent Documents

-   [Non-patent Document 1] Journal of the American Chemical Society,    128, 8412-8413(2006)-   [Non-patent Document 2] Journal of the American Chemical Society,    133, 6497-6500(2011)-   [Non-patent Document 3] Chemical & Pharmaceutical Bulletin, 59,    1570-1573(2011)-   [Non-patent Document 4] Synthesis, 20, 3545-3555(2010)-   [Non-patent Document 5] Journal of Organic Chemistry, 64,    2564-2566(1999)

SUMMARY OF INVENTION Problems that the Invention is to Solve

The present inventors have studied, by using various oxidationcatalysts, the safety and reaction efficiency of an oxidation method of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (which may hereinafter be abbreviated as “Compound(EM)”) for safely and efficiently obtaining3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester (which may hereinafter be abbreviated as “Compound(FK)”) which is a synthesis intermediate of3-[(45)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]-benzodiazepin-4-yl]propionicacid methyl ester benzenesulfonate (which may hereinafter be abbreviatedas “Compound (P)”) having sedative and anesthetic actions. The studysuggested that a good result can be obtained by using AZADO(2-azaadamantane-N-oxyl) that similar to TEMPO, belongs to N-oxyloxidation catalysts. It has however been revealed that when an oxidationreaction using AZADO is repeated, reproducibility of a conversion rate(reaction efficiency) cannot be achieved for some reasons in spite ofthe reaction repeated under the same conditions.

In short, an object of the present invention is to find a reason whyreproducibility of a conversion rate (reaction efficiency) cannot beachieved in an oxidation reaction using AZADO and establish an oxidationmethod of Compound (EM) which is capable of preparing Compound (FK) at ahigh conversion rate (reaction efficiency) with good reproducibility,safe, highly efficient, and applicable to industrial production.

Means for Solving the Problems

With a view to achieving the above-mentioned object, the presentinventors have extensively studied the reason why the reproducibility ofa conversion rate (reaction efficiency) was not achieved in an oxidationreaction using AZADO. As a result, it has been found that a slightamount of an ammonium ion mixed in the reaction system impedes theoxidation reaction. The study has been made further to find that anoxidation reaction is conducted at a high conversion rate (reactionefficiency) with excellent reproducibility by reducing the amount of anammonium ion present in the reaction system to a certain amount or less;that reduction of the amount of an ammonium ion can be applied not onlyto oxidation reactions using AZADO but also to general oxidationreactions using AZADO analogs; and that this reduction can be appliedeven to general oxidation reactions using N-oxyl oxidation catalystsincluding TEMPO, leading to the completion of the present invention.

Described specifically, the present invention relates to:

[1] a process for preparing3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester (Compound (FK)) by subjecting, to an oxidationreaction, a compound selected from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (“Compound (EM)”),3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (which may hereinafter be abbreviated as “Compound(E)”), and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (which may hereinafter be abbreviated as “Compound(E′)”) in the presence of at least one oxidation catalyst selected fromthe group consisting of a compound represented by the following formula(I-1), (I-2) or (I-3):

(wherein, R₁, R₂, and R₅ each independently represent a hydrogen atom, ahalogen, a hydroxyl group, a C₁₋₃ alkyl group, or a C₁₋₃ alkoxy group,R₃ represents a hydrogen atom or a halogen, and

represents N—O^(•), N—OH, or N⁺═O), 2,2,6,6-tetramethylpiperidin-N-oxyl,2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxyl, and2,2,6,6-tetramethyl-1,4-piperidinediol, salts thereof, and solvatesthereof,

wherein the oxidation reaction is conducted in a reaction systemsatisfying at least one of the following conditions (a) to (c):

(a) in the absence of an ammonium ion,

(b) in the presence of an ammonium ion in a weight ratio of 170 ppm orless relative to the compound selected from the group consisting ofCompound (EM), Compound (E), and Compound (E′) as a compound to besubjected to the oxidation reaction, and

(c) in the presence of an ammonium ion in a molar ratio of 145% or lessrelative to the oxidation catalyst;

[2] the preparation process as described above in [1], wherein thecompound selected from the group consisting of Compound (EM), Compound(E), and Compound (E′) is an unpurified compound;

[3] the preparation process as described above in [1] or [2], whereinthe oxidation reaction is conducted at a conversion rate of 98% or more;

[4] the preparation process as described above in any one of [1] to [3],wherein Compound (EM) is obtained by conducting an addition reactionbetween3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester (which may hereinafter be abbreviated as “Compound(D)”) and 1-aminopropan-2-ol, followed by washing;

[5] the preparation process as described above in any one of [1] to [3],wherein Compound (E) is obtained by conducting an addition reactionbetween Compound (D) and (R)-1-aminopropan-2-ol, followed by washing;

[6] the preparation process as described above in any one of [1] to [3],wherein Compound (E′) is obtained by conducting an addition reactionbetween Compound (D) and (S)-1-aminopropan-2-ol, followed by washing;

[7] the preparation process as described above in any one of [4] to [6],wherein washing is conducted with a water soluble solution having a pHof from about 3.5 to about 10.5;

[8] the preparation process as described above in [7], wherein the watersoluble solution is an aqueous solution of ammonium chloride, an aqueoussolution of sodium monohydrogen phosphate, an aqueous solution of sodiumdihydrogen phosphate, and/or a phosphate buffer;

[9] the preparation process as described above in any one of [1] to [8],wherein the oxidation catalyst is either 2-azaadamantane-N-oxyl or2-azaadamantan-2-ol;

[10] a process for preparing Compound (FK) by subjecting Compound (E) toan oxidation reaction in the presence of an oxidation catalyst which iseither 2-azaadamantane-N-oxyl or 2-azaadamantan-2-ol, wherein theCompound (E) is a compound obtained by conducting an addition reactionbetween Compound (D) and (R)-1-aminopropan-2-ol, followed by washingwith a phosphate buffer;

[11] the preparation process as described above in [10], whereinCompound (E) is an unpurified compound;

[12] Compound (FK), obtained by subjecting a compound selected from thegroup consisting of Compound (EM), Compound (E), and Compound (E′) to anoxidation reaction in the presence of at least one oxidation catalystselected from the group consisting of a compound represented by thefollowing formula (I-1), (I-2) or (I-3):

(wherein, all the symbols have the same meanings as described above in[1]), 2,2,6,6-tetramethylpiperidin-N-oxyl,2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxyl, and2,2,6,6-tetramethyl-1,4-piperidinediol, salts thereof, and solvatesthereof,

wherein the oxidation reaction is conducted in a reaction systemsatisfying at least one of the following conditions (a) to (c):

(a) in the absence of an ammonium ion,

(b) in the presence of an ammonium ion in a weight ratio of 170 ppm orless relative to the compound selected from the group consisting ofCompound (EM), Compound (E), and Compound (E′) as a compound to besubjected to the oxidation reaction, and

(c) in the presence of an ammonium ion in a molar ratio of 145% or lessrelative to the oxidation catalyst;

[13] Compound (FK) as described above in [12], wherein the compoundselected from the group consisting of Compound (EM), Compound (E), andCompound (E′) is an unpurified compound;

[14] Compound (FK) as describe above in [12] or [13], wherein theoxidation reaction is conducted at a conversion rate of 98% or more;

[15] Compound (FK) as described above in any one of [12] to [14],wherein Compound (EM) is obtained by conducting an addition reactionbetween Compound (D) and 1-aminopropan-2-ol, followed by washing;

[16] Compound (FK) as described above in any one of [12] to [14],wherein Compound (E) is obtained by conducting an addition reactionbetween Compound (D) and (R)-1-aminopropan-2-ol, followed by washing;

[17] Compound (FK) as described above in any one of [12] to [14],wherein Compound (E′) is obtained by conducting an addition reactionbetween Compound (D) and (S)-1-aminopropan-2-ol, followed by washing;

[18] Compound (FK) as described above in any one of [15] to [17],wherein washing is conducted with a water soluble solution having a pHof from about 3.5 to about 10.5;

[19] Compound (FK) as described above in [18], wherein the water solublesolution is an aqueous solution of ammonium chloride, an aqueoussolution of sodium monohydrogen phosphate, an aqueous solution of sodiumdihydrogen phosphate, and/or a phosphate buffer;

[20] Compound (FK) as described above in any one of [12] to [19],wherein the oxidation catalyst is either 2-azaadamantane-N-oxyl or2-azaadamantan-2-ol;

[21]3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionicacid methyl ester benzenesulfonate (Compound (P)), obtained by thefollowing steps (i) to (iii):

(i) a step of conducting an addition reaction between Compound (D) and(R)-1-aminopropan-2-ol and then washing with a phosphate buffer toobtain Compound (E);

(ii) a step of subjecting Compound (E) obtained in the step (i) to anoxidation reaction in the presence of an oxidation catalyst which iseither 2-azaadamantane-N-oxyl or 2-azaadamantan-2-ol to obtain Compound(FK); and

(iii) a step of reacting Compound (FK) obtained in the step (ii) withbenzenesulfonic acid to obtain Compound (P);

[22] Compound (P) as described above in [21], wherein Compound (E) is anunpurified compound;

[23] a reaction composition containing a compound selected from thegroup consisting of Compound (EM), Compound (E), and Compound (E′), anoxidizing agent, an oxidation catalyst, and a solvent, which contains noammonium ion or contains an ammonium ion in a weight ratio of 170 ppm orless relative to the compound selected from the group consisting ofCompound (EM), Compound (E), and Compound (E′) as the compound to besubjected to the oxidation reaction or in a molar ratio of 145% or lessrelative to the oxidation catalyst;

[24] the reaction composition as described above in [23], for thepreparation of Compound (FK);

[25] the reaction composition as described above in [23] or [24],wherein the oxidation catalyst is selected from the group consisting ofa compound represented by the following formula (I-1), (I-2) or (I-3):

(wherein, all the symbols have the same meanings as described above in[1]), 2,2,6,6-tetramethylpiperidin-N-oxyl,2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxyl, and2,2,6,6-tetramethyl-1,4-piperidinediol, salts thereof, and solvatesthereof.

Effect of the Invention

According to the present invention, Compound (FK) can be prepared from acompound selected from the group consisting of Compound (EM), Compound(E), and Compound (E′), even if the compound is an unpurified compound,at a markedly high conversion rate and/or oxidation catalyst efficiencywith good reproducibility. Described specifically, Compound (FK) can beprepared with good reproducibility and high efficiency by using as astarting material Compound (EM) whose ammonium ion remaining content hasbeen defined and subjecting it to an oxidation reaction while usingTEMPO, 2-azaadamantane-N-oxyl (which may hereinafter be abbreviated as“AZADO”) or an analog thereof, which will be described later as anoxidation catalyst. This Compound (FK) is an important synthesisintermediate of Compound (P) having both sedative and anestheticactions. Since the preparation process of the present invention canstably supply Compound (FK) safely and with good reproducibility withoutconducting a particular purification step, it is very useful from thestandpoint of industrial productivity of Compound (P) which is an activepharmaceutical ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting an ammonium ion content and a conversion ratefrom Compound (E) to Compound (FK) in the present invention; and

FIG. 2 is a graph showing both the graph of FIG. 1 and an approximatecurve (linear approximation).

MODE FOR CARRYING OUT THE INVENTION

The present invention will hereinafter be described in detail.

In the present invention,“3-[(45)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]-benzodiazepin-4-yl]propionicacid methyl ester benzenesulfonate (Compound (P))” is a compound havinga structure represented by the following formula:

In the present invention,“3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester (Compound (FK))” is a compound having a structurerepresented by the following formula:

In the present invention,“3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (Compound (EM))” is a compound having a structurerepresented by the following formula:

and is a mixture having, at any ratio, Compound (E) and Compound (E′)which will be described later.

In the present invention,“3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (Compound (E))” is a compound having a structurerepresented by the following formula:

In the present invention,“3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (Compound (E′))” is a compound having a structurerepresented by the following formula:

In the present invention,“3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester (Compound (D))” is a compound having a structurerepresented by the following formula:

In the present invention, the term “halogen” means fluorine, chlorine,bromine, or iodine. In the present invention, the term “C₁₋₃ alkylgroup” means methyl, ethyl, n-propyl, or isopropyl.

In the present invention, the term “C₁₋₃ alkoxy group” means methoxy,ethoxy, n-propoxy, or isopropoxy.

In the present invention, examples of the compound represented by theformula (I-1) include AZADO (another name:2-azatricyclo[3.3.1.1^(3,7)]dec-2-yloxidanyl):

2-azaadamantane-N-oxoammonium cation (another name:2-oxo-2-azoniatricyclo[3.3.1.1^(3,7)]decane) (which may hereinafter beabbreviated as “AZADO cation”):

2-azaadamantan-2-ol (another name:2-azatricyclo[3.3.1.1^(3,7)]decan-2-ol) (which may hereinafter beabbreviated as “AZADOH”):

1-methyl-2-azaadamantan-N-oxyl (another name:(1-methyl-2-azatricyclo[3.3.1.1^(3,7)]dec-2-yl)oxidanyl) (which mayhereinafter be abbreviated as “Me-AZADO”):

1-methyl-2-azaadamantane-N-oxoammonium cation (another name:1-methyl-2-oxo-2-azoniatricyclo[3.3.1.1^(3,7)]decane) (which mayhereinafter be abbreviated as “Me-AZADO cation”):

1-methyl-2-azaadamantan-2-ol (another name:1-methyl-2-azatricyclo[3.3.1.1^(3,7)]decan-2-ol) (which may hereinafterbe abbreviated as “Me-AZADOH):

5-hydroxy-1-methyl-2-azaadamantane-N-oxyl (another name:(5-hydroxy-1-methyl-2-azatricyclo[3.3.1.1^(3,7)]dec-2-yl)oxidanyl)(which may hereinafter be abbreviated as “5-OH-1-Me-AZADO”:

5-hydroxy-1-methyl-2-azaadamantane-N-oxoammonium cation (another name:5-hydroxy-1-methyl-2-oxo-2-azoniatricyclo[3.3.1.1^(3,7)]decane) (whichmay hereinafter abbreviated as “5-OH-1-Me-AZADO cation”):

5-hydroxy-1-methyl-2-azaadamantan-2-ol (another name:1-methyl-2-azatricyclo[3.3.1.1^(3,7)]decane-2,5-diol) (which mayhereinafter be abbreviated as “5-OH-1-Me-AZADOH”):

5-methoxy-1-methyl-2-azaadamantane-N-oxyl (another name:(5-methoxy-1-methyl-2-azatricyclo[3.3.1.1^(3,7)]dec-2-yl)oxidanyl)(which may hereinafter be abbreviated as “5-MeO-1-Me-AZADO”):

5-methoxy-1-methyl-2-azaadamantane-N-oxoammonium cation (another name:(5-methoxy-1-methyl-2-oxo-2-azoniatricyclo[3.3.1.1^(3,7)]decane) (whichmay hereinafter be abbreviated as “5-MeO-1-Me-AZADO cation”):

5-methoxy-1-methyl-2-azaadamantan-2-ol (another name:(5-methoxy-1-methyl-2-azatricyclo[3.3.1.1^(3,7)]decan-2-ol) (which mayhereinafter be abbreviated as “5-MeO-1-Me-AZADOH”):

5-fluoro-1-methyl-2-azaadamantane-N-oxyl (another name:(5-fluoro-1-methyl-2-azatricyclo[3.3.1.1^(3,7)]dec-2-yl)oxidanyl) (whichmay hereinafter be abbreviated as “5-F-1-Me-AZADO”):

5-fluoro-1-methyl-2-azaadamantane-N-oxoammonium cation (another name:(5-fluoro-1-methyl-2-oxo-2-azoniatricyclo[3.3.1.1^(3,7)]decane) (whichmay hereinafter be abbreviated as “5-F-1-Me-AZADO cation):

5-fluoro-1-methyl-2-azaadamantan-2-ol (another name:5-fluoro-1-methyl-2-azatricyclo[3.3.1.1^(3,7)]decan-2-ol) (which mayhereinafter be abbreviated as “5-F-1-Me-AZADOH”):

1-fluoro-2-azaadamantane-N-oxyl (another name:(1-fluoro-2-azatricyclo[3.3.1.1^(3,7)]dec-2-yl)oxidanyl) (which mayhereinafter be abbreviated as “1-F-AZADO”):

1-fluoro-2-azaadamantane-N-oxoammonium cation (another name:1-fluoro-2-oxo-azoniatricyclo[3.3.1.1^(3,7)]decane) (which mayhereinafter be abbreviated as “1-F-AZADO cation”):

1-fluoro-2-azaadamantan-2-ol (another name:1-fluoro-2-azatricyclo[3.3.1.1^(3,7)]decan-2-ol) (which may hereinafterbe abbreviated as “1-F-AZADOH”):

5-fluoro-2-azaadamantane-N-oxyl (another name:(5-fluoro-2-azatricyclo[3.3.1.1^(3,7)]dec-2-yl)oxidanyl) (which mayhereinafter be abbreviated as “5-F-AZADO”):

5-fluoro-2-azaadamantane-N-oxoammonium cation (another name:5-fluoro-2-oxo-azoniatricyclo[3.3.1.1^(3,7)]decane) (which mayhereinafter be abbreviated as “5-F-AZADO cation”):

5-fluoro-2-azaadamantan-2-ol (another name:5-fluoro-2-azatricyclo[3.3.1.1^(3,7)]decan-2-ol) (which may hereinafterbe abbreviated as “5-F-AZADOH”):

5,7-difluoro-1-methyl-2-azaadamantane-N-oxyl (another name:(5,7-difluoro-1-methyl-2-azatricyclo[3.3.1.1^(3,7)]dec-2-yl)oxidanyl)(which may hereinafter be abbreviated as “5,7-diF-1-Me-AZADO”):

5,7-difluoro-1-methyl-2-azaadamantane-N-oxoammonium cation (anothername:(5,7-difluoro-1-methyl-2-oxo-2-azoniatricyclo[3.3.1.1^(3,7)]decane)(which may hereinafter be abbreviated as “5,7-diF-1-Me-AZADO cation”):

5,7-difluoro-1-methyl-2-azaadamantan-2-ol (another name:5,7-difluoro-1-methyl-2-azatricyclo[3.3.1.1^(3,7)]decan-2-ol) (which mayhereinafter be abbreviated as “5,7-diF-1-Me-AZADOH):

1,3-dimethyl-2-azaadamantane-N-oxyl (another name:(1,3-dimethyl-2-azatricyclo[3.3.1.1^(3,7)]dec-2-yl)oxidanyl) (which mayhereinafter be abbreviated as “1,3-diMe-AZADO”):

1,3-dimethyl-2-azaadamantane-N-oxoammonium cation (another name:1,3-dimethyl-2-oxo-2-azoniatricyclo[3.3.1.1^(3,7)]decane) (which mayhereinafter be abbreviated as “1,3-diMe-AZADO cation):

and 1,3-dimethyl-2-azaadamantan-2-ol (another name:1,3-dimethyl-2-azatricyclo[3.3.1.1^(3,7)]decan-2-ol) (which mayhereinafter be abbreviated as “1,3-diMe-AZADOH”):

In the present invention, the compound represented by the formula (I-2)include 9-aza-noradamantane-N-oxyl (another name:octahydro-2,5-epimino-pentalen-7-yloxidanyl) (which may hereinafter beabbreviated as “Nor-AZADO”):

9-aza-noradamantane-N-oxoammonium cation (another name:7-oxooctahydro-2,5-epiminopentalenium) (which may hereinafter beabbreviated as “Nor-AZADO cation”):

and 9-aza-noradamantan-9-ol (another name:octahydro-2,5-epimino-pentalen-7-ol) (which may hereinafter beabbreviated as “Nor-AZADOH”):

In the present invention, the compound represented by the formula (I-3)include 9-azabicyclo-[3.3.1]nonane-N-oxyl (another name:9-azabicyclo[3.3.1]non-9-yloxidanyl) (which may hereinafter beabbreviated as “ABNO”):

9-azabicyclo-[3.3.1]nonane-N-oxoammonium cation (another name:9-oxo-9-azoniabicyclo[3.3.1]nonane) (which may hereinafter beabbreviated as “ABNO cation”):

and 9-azabicyclo-[3.3.1]nonan-9-ol (another name:9-azabicyclo[3.3.1]nonan-9-ol) (which may hereinafter be abbreviated as“ABNOH”):

In the present invention, “2,2,6,6-tetramethylpiperidine-N-oxyl” is acompound having a structure represented by the following formula:

In the present invention, “2,2,6,6-tetramethylpiperidin-1-ol” is acompound having a structure represented by the following formula:

In the present invention,“4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl” is a compound having astructure represented by the following formula:

In the present invention, “2,2,6,6-tetramethyl-1,4-piperidinediol” is acompound having a structure represented by the following formula:

In the present invention, the term “AZADO analogs” means compoundsrepresented by the formula (I-1), (I-2), and (I-3), salts thereof, andsolvates thereof.

In the present invention, the term “oxidation catalyst” means an N-oxyloxidation catalyst and examples include the above-mentioned AZADOanalogs and 2,2,6,6-tetramethylpiperidine-N-oxyl,2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, and2,2,6,6-tetramethyl-1,4-piperidinediol, salts thereof, and solventsthereof. These oxidation catalysts are reagents to be used in anoxidation reaction for synthesizing a ketone compound from an alcoholcompound.

In the present invention, the term “weight ratio” means a proportion(ratio) of the weight of a certain substance relative to the weight of astandard substance. For example, the phrase “in the presence of anammonium ion in a weight ratio of 170 ppm or less relative to Compound(EM)” means that “in the presence of an ammonium ion in an amount of 170μg or less per 1 g of Compound (EM)”.

In the present invention, the term “molar ratio” means a proportion(percentage) of the number of moles of a certain substance relative tothe number of moles of a standard substance. For example, the phrase “inthe presence of an ammonium ion in a molar ratio of 145% or lessrelative to the oxidation catalyst” means that “in the presence of anammonium ion in an amount of 1.45 mol or less per 1 mol of the oxidationcatalyst”.

In the present invention, the term “unpurified” means that Compound(EM), Compound (E) or Compound (E′) obtained by an organic reaction suchas addition reaction has not been purified, more specifically,impurities (such as organic matters (for example, an organic compound(byproduct) other than the target compound, an organic compound which isa starting material that has remained after the reaction, and an organicreagent), inorganic matters (for example, sodium chloride, ammoniumchloride, sodium hydroxide, and potassium hydroxide), and inorganic ions(for example, a cation such as sodium ion, potassium ion, lithium ion,and ammonium ion and an anion such as chloride ion and bromide ion) havenot been removed by a conventional purification method, for example,distillation under reduced pressure, high-performance liquidchromatography using silica gel or magnesium silicate, thin-layerchromatography, ion exchange resin, scavenger resin, columnchromatography, or recrystallization, or desalting treatment for notonly removing organic matters which are impurities but also removinginorganic matters or inorganic ions.

In the present invention, the term “conversion rate” means a percent ofan original certain substance (raw material) which has been convertedinto another substance by a chemical reaction, based on the number ofmoles of the original certain substance (raw material). For example, thephrase “a preparation process that has provided a conversion rate of98%” means “a preparation process in which 98% of a substance used as araw material has been converted into another substance on the basis ofthe number of moles”, in other words, “a preparation process in which 2%of a substance used as a raw material has remained on the basis of thenumber of moles”.

In the present invention, the term “phosphate buffer” means a solutionobtained by mixing an aqueous solution of sodium dihydrogen phosphateand an aqueous solution of sodium monohydrogen phosphate at any ratioand the mixed solution has a pH of from about 5.8 to 8.0.

In the present invention, examples of the “oxidizing agent” includesodium hypochlorite (NaOCl), sodium chlorite (NaClO₂), sodium bromite(NaBrO₂), calcium hypochlorite (Ca(OCl)₂), Oxone (trade mark),metachloroperbenzoic acid (MCPBA), iodosylbenzene (PhI═O), iodobenzenediacetate (PhI(OAc)₂), orthoperiodic acid (H₅IO₆), potassiumferricyanide (K₃[Fe(CN)₆]), and N-chlorosuccinic acid imide (NCS).

In the present invention, the “solvent” in “the reaction compositioncontaining a compound selected from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, an oxidizing agent, an oxidation catalyst, and asolvent”, that is, the “solvent” to be used in the oxidation reaction isan organic solvent (for example, ethyl acetate, methyl acetate, toluene,methylene chloride, dichloroethane, acetonitrile, dimethylsulfoxide, oracetone, or a solvent obtained by mixing these organic solvents asneeded) or a mixed solvent of the above-mentioned organic solvent andwater.

In the present invention, the term “reaction composition” means anassembly of organic matters and inorganic matters present in thereaction system of a chemical reaction. For example, in an oxidationreaction, the reaction composition of the oxidation reaction contains astarting material, a reaction reagent (such as oxidizing agent), areaction catalyst (such as oxidation catalyst), and a solvent and it mayfurther contain an inorganic salt (such as ammonium chloride, ammoniumbromide, ammonium acetate, ammonium carbonate, sodium monohydrogenphosphate, and sodium dihydrogen phosphate), and an inorganic ion (suchas ammonium ion, chloride ion, bromide ion, acetate ion, carbonate ion,phosphate ion, and sodium ion).

In the present invention, R₁ is preferably hydrogen, fluorine, ormethyl, more preferably hydrogen or methyl, particularly preferablyhydrogen.

In the present invention, R₂ is preferably hydrogen, fluorine, ahydroxyl group, or methoxy, more preferably hydrogen.

In the present invention, R₃ is preferably hydrogen or fluorine, morepreferably hydrogen.

In the present invention, R₅ is preferably hydrogen or methyl, morepreferably hydrogen.

In the present invention, X is preferably nitrogen (N) or an ammoniumcation (N⁺), more preferably nitrogen.

In the present invention, R₄ is preferably an oxygen radical (O^(•)), ahydroxyl group (OH), or oxygen (O), more preferably an oxygen radical ora hydroxyl group, particularly preferably a hydroxyl group.

In the present invention,

is a single bond or a double bond, preferably a single bond.

In the present invention,

is preferably

N—O^(•) or N—OH,

more preferably

N—OH.

In the intention, the compound represented by the formula (I-1) ispreferably AZADO, AZADO cation, AZADOH, Me-AZADO, Me-AZADO cation,Me-AZADOH, 5-OH-1-Me-AZADO, 5-OH-1-Me-AZADO cation, 5-OH-1-Me-AZADOH,5-MeO-1-Me-AZADO, 5-MeO-1-Me-AZADO cation, 5-MeO-1-Me-AZADOH,5-F-1-Me-AZADO, 5-F-1-Me-AZADO cation, 5-F-1-Me-AZADOH, 1-F-AZADO,1-F-AZADO cation, 1-F-AZADOH, 5-F-AZADO, 5-F-AZADO cation, 5-F-AZADOH,5,7-diF-1-Me-AZADO, 5,7-diF-1-Me-AZADO cation, 5,7-diF-1-Me-AZADOH,1,3-diMe-AZADO, 1,3-diMe-AZADO cation, or 1,3-diMe-AZADOH, morepreferably AZADO, AZADO cation, AZADOH, Me-AZADO, Me-AZADO cation, orMe-AZADOH, still more preferably AZADO, AZADO cation, or AZADOH, stillmore preferably AZADO or AZADOH, particularly preferably AZADOH.

In the present invention, the compound represented by the formula (I-2)is preferably Nor-AZADO, Nor-AZADO cation, or Nor-AZADOH, morepreferably Nor-AZADO.

In the present invention, the compound represented by the formula (I-3)is preferably ABNO, ABNO cation, or ABNOH, more preferably ABNO.

In the present invention, the oxidation catalyst is preferably AZADO,AZADO cation, AZADOH, Me-AZADO, Me-AZADO cation, Me-AZADOH,5-OH-1-Me-AZADO, 5-OH-1-Me-AZADO cation, 5-OH-1-Me-AZADOH,5-MeO-1-Me-AZADO, 5-MeO-1-Me-AZADO cation, 5-MeO-1-Me-AZADOH,5-F-1-Me-AZADO, 5-F-1-Me-AZADO cation, 5-F-1-Me-AZADOH, 1-F-AZADO,1-F-AZADO cation, 1-F-AZADOH, 5-F-AZADO, 5-F-AZADO cation, 5-F-AZADOH,5,7-diF-1-Me-AZADO, 5,7-diF-1-Me-AZADO cation, 5,7-diF-1-Me-AZADOH,1,3-diMe-AZADO, 1,3-diMe-AZADO cation, 1,3-diMe-AZADOH, Nor-AZADO,Nor-AZADO cation, Nor-AZADOH, ABNO, ABNO cation, or ABNOH, morepreferably AZADO, AZADO cation, AZADOH, Me-AZADO, Me-AZADO cation,Me-AZADOH, Nor-AZADO, or ABNO, still more preferably AZADO, AZADOcation, or AZADOH, still more preferably AZADO or AZADOH, particularlypreferably AZADOH.

In the present invention, the conversion rate is preferably 98% or more,more preferably 98.5% or more, still more preferably 99% or more, stillmore preferably 99.5% or more, particularly preferably 100%.

In the present invention, in order to attain the conversion rate fallingwithin the above-mentioned preferred range, it is recommended, in thereaction system of the oxidation reaction, to adjust the weight ratio ofan ammonium ion, relative to each of Compound (EM), Compound (E), andCompound (E′), to a predetermined level or less; to adjust the molarratio of an ammonium ion relative to the oxidation catalyst to apredetermined level or less; or to satisfy both.

The weight ratio of an ammonium ion relative to each of Compound (EM),Compound (E), and Compound (E′) is at least about 170 ppm or less,preferably about 111 ppm or less, more preferably about 91 ppm or less,still more preferably about 72 ppm or less, still more preferably about53 ppm or less, particularly preferably about 33 ppm or less.

The molar ratio of an ammonium ion relative to the oxidation catalyst isat least about 145% or less, preferably about 94% or less, morepreferably about 78% or less, still more preferably about 61% or less,still more preferably about 45% or less, particularly preferably about28% or less.

Compound (FK) can be obtained from each of Compound (EM), Compound (E),and Compound (E′) at the above-mentioned preferable conversion rate byadjusting the weight ratio of an ammonium ion relative to each ofCompound (EM), Compound (E), and Compound (E′) to fall within theabove-mentioned range, by adjusting the molar ratio of an ammonium ionrelative to the oxidation catalyst to fall within the above-mentionedrange, or by satisfying both.

In the present invention, Compound (EM) to be used in the oxidationreaction is preferably obtained by conducting an addition reactionbetween Compound (D) and 1-aminopropan-2-ol and then washing.

In the present invention, Compound (E) to be used in the oxidationreaction is preferably obtained by conducting an addition reactionbetween Compound (D) and (R)-1-aminopropan-2-ol and then washing.

In the present invention, Compound (E′) to be used in the oxidationreaction is preferably obtained by conducting an addition reactionbetween Compound (D) and (S)-1-aminopropan-2-ol or and then washing.

In the present invention, the term “washing” in the phrase “obtained byconducting an addition reaction between Compound (D) and1-aminopropan-2-ol, (R)-1-aminopropan-2-ol, or (S)-1-aminopropan-2-oland then washing” means a work-up operation, which is to be conductedafter the addition reaction, with a solution having a pH near a weaklyacidic to weakly basic range (from about pH 3.5 to about pH 10.5,preferably from about pH 4.5 to about pH 9.0), particularly preferably apH near a weakly acidic to neutral range (from about pH 5.5 to about pH8.0) and having a buffer action. The solution used for washing is awater soluble solution and examples include an aqueous solution ofammonium chloride (from about pH 4.5 to pH 6.0), an aqueous solution ofsodium monohydrogen phosphate (about pH 9.5), an aqueous solution ofsodium dihydrogen phosphate (from about pH 3.8 to about pH 4.5), aphosphate buffer (from about pH 5.8 to about pH 8.0), a potassiumphosphate buffer (about pH 10.0), a phosphate buffer saline (about pH7.4), an acetate buffer (acetic acid+sodium acetate; from about pH 3.6to pH 5.6), a citrate buffer (citric acid+sodium citrate; from about pH3.0 to about pH 6.2), a citrate-phosphate buffer (from about pH 2.6 toabout pH 7.0), a borate buffer (from about pH 8.0 to about pH 10.3), anda tartrate buffer (from about pH 2.9 to about pH 4.2).

In the present invention, a washing method is preferably a method ofwashing with an aqueous solution of ammonium chloride, an aqueoussolution of sodium dihydrogen phosphate, an aqueous solution of sodiummonohydrogen phosphate, or a phosphate buffer (a mixed solution obtainedby mixing an aqueous solution of sodium dihydrogen phosphate and anaqueous solution of sodium monohydrogen phosphate at any ratio); morepreferably a method of washing with an aqueous solution of sodiumdihydrogen phosphate, an aqueous solution of sodium monohydrogenphosphate, or a phosphate buffer; still more preferably, a method ofwashing with an aqueous solution of sodium dihydrogen phosphate or aphosphate buffer; particularly preferably a method of washing with aphosphate buffer.

In the present invention, as is apparent for those skilled in the art,the symbol:

represents bonding to the opposite side of the paper plane (that is,α-configuration); the symbol:

represents bonding to the near side of the paper plane (that is,β-configuration); the symbol:

represents α-configuration or β-configuration; and the symbol:

represents a mixture of the α-configuration and the β-configuration atany ratio, unless otherwise noted.

[Salt]

The compound represented by the formula (I-1), (I-2), or (I-3),2,2,6,6-tetramethylpiperidine-N-oxyl, 2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, or2,2,6,6-tetramethyl-1,4-piperidinediol is converted into a salt thereofby a known method.

The salt is preferably a pharmaceutically acceptable salt.

The salt is preferably water soluble.

Examples of the salt include acid addition salts.

Examples of the acid addition salts include inorganic acid salts such ashydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate,borate, tetrafluoroborate, perchlorate, antimonate, andhexafluorophosphate and organic acid salts such as acetate, lactate,tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate,trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate,glucuronate, and gluconate.

In the present invention, the acid addition salt is preferably aninorganic acid salt or an acetate, more preferably, a hydrochloride, ahydrobromide, a hydroiodide, a sulfate, a phosphate, a nitrate, aborate, a tetrafluoroborate, a perchlorate, an antimonate, ahexafluorophosphate, or an acetate, particularly preferably ahydrochloride, a nitrate, a tetrafluoroborate, or an acetate.

[Solvate]

The compound represented by the formula (I-1), (I-2), or (I-3),2,2,6,6-tetramethylpiperidine-N-oxyl, 2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, or2,2,6,6-tetramethyl-1,4-piperidinediol, or a salt thereof is convertedinto a solvate thereof by a known method. The solvate is preferablynontoxic and water soluble. Examples of the suitable solvate includesolvates with water or an alcoholic solvent (for example, ethanol).

Atoms each constituting Compound (D), Compound (EM), Compound (E),Compound (E′), Compound (FK), Compound (P), the formula (I-1), theformula (I-2), and the formula (I-3) may be substituted by an isotopethereof (for example, ²H, ³H, ¹³C_(,) ¹⁴C, ¹⁵N, ¹⁶N, ¹⁷O or ¹⁸O).

The preparation process according to the present invention will next bedescribed. First, a process for preparing Compound (FK) from Compound(EM) according to the present invention is shown by the followingreaction scheme 1.

Compound (EM) can be prepared readily by a known method, for example, amethod shown below in the reaction scheme 2, a method based thereon, themethod described in “Comprehensive Organic Transformations: A Guide toFunctional Group Preparations 2nd Edition (Richard C. Larock, John Wiley& Sons Inc, 1999)”, or the method described in WO 2000/069836.

Incidentally, Compound (EM) may be used as a salt thereof.

As such a salt, a pharmaceutically acceptable salt, for example, an acidaddition salt may be used.

As the acid addition salt, for example, those described as an acidaddition salt in the above column [salt] may be used.

Compound (EM) or salt thereof used in the reaction scheme 1 may be usedas a solvate thereof.

Examples of the solvate include solvates with water or with an alcoholicsolvent (for example, ethanol).

In the oxidation reaction for preparing Compound (FK) from Compound (EM)described in the reaction scheme 1, using an unpurified Compound (EM) isnovel. In addition, using an AZADO analog as an oxidation catalyst to beused in the oxidation reaction for preparing Compound (FK) from Compound(EM) is novel. Compound (FK) available by this reaction can be prepared,for example, by reacting Compound (EM) which may be unpurified at atemperature of from about −20° C. to 50° C. in an organic solvent (forexample, ethyl acetate, methyl acetate, toluene, methylene chloride,dichloroethane, acetonitrile, dimethylsulfoxide, or acetone, or asolvent obtained by mixing the above-mentioned organic solvents asneeded) or a mixed solvent of such an organic solvent and water, in thepresence or absence of a base (for example, sodium hydrogen carbonate,sodium carbonate, 1,4-diazabicyclo[2.2.2]octane, or potassium hydroxide,or a base obtained by mixing the above-mentioned bases as needed) or anaqueous solution of such a base, in the presence or absence of aninorganic salt (for example, sodium bromide, potassium bromide,potassium chloride, copper chloride, copper bromide, butylammoniumbromide, butylammonium chloride, sodium nitrite, or sodium acetate, oran inorganic salt obtained by mixing these inorganic salts as needed),and in the presence of an oxidizing agent (for example, sodiumhypochlorite (NaOCl), sodium chlorite (NaClO₂), sodium hypobromite(NaBrO₂), calcium hypochlorite (Ca(OCl)₂), Oxone (trade mark),metachloroperbenzoic acid (MCPBA), iodosylbenzene (PhI═O), iodobenzenediacetate (PhI(OAc)₂), orthoperiodic acid (H₅IO₆), potassiumferricyanide (K₃[Fe(CN)₆]), or N-chlorosuccinic acid imide (NCS), or anoxidizing agent obtained by mixing the above-mentioned oxidizing agentsas needed) and the above-mentioned oxidation catalyst (for example,AZADO analogs (for example, AZADO, Me-AZADO, AZADOH, Nor-AZADO, or ABNO,or an oxidation catalyst obtained by mixing the above-mentionedoxidation catalysts as needed)).

As another process, Compound (FK) can be prepared, for example, bysubjecting Compound (EM) which may be unpurified to an air (oxygen)oxidation reaction at a temperature of from about 0° C. to 80° C. in anorganic solvent (for example, ethyl acetate, toluene, methylenechloride, dichloroethane, acetonitrile, dimethylsulfoxide, acetone, oracetic acid, or a solvent obtained by mixing the above-mentioned organicsolvents as needed) or a mixed solvent of such an organic solvent andwater, in the presence or absence of a base (for example, sodiumhydrogen carbonate, sodium carbonate, 1,4-diazabicyclo[2.2.2]octane, orpotassium hydroxide, or a base obtained by mixing these bases as needed)or an aqueous solution of such a base, in the presence or absence of aninorganic salt (for example, sodium bromide, potassium bromide,potassium chloride, copper chloride, copper bromide, butylammoniumbromide, or butylammonium chloride, or an inorganic salt obtained bymixing the above-mentioned inorganic salts as needed), in the presenceof the above-mentioned oxidation catalyst (for example, AZADO analogs(for example, AZADO, Me-AZADO, AZADOH, Nor-AZADO, or ABNO, or anoxidation catalyst obtained by mixing the above-mentioned oxidationcatalysts as needed).

As a further process, Compound (FK) can be prepared by subjecting,instead of Compound (EM), Compound (E) or Compound (E′) to theabove-mentioned oxidation reaction.

The compound subjected to the oxidation reaction in the presentinvention is preferably Compound (E) or Compound (E′), more preferablyCompound (E).

Compound (EM) can be prepared, for example, by the process shown in thefollowing reaction scheme 2.

The reaction for preparing Compound (EM) from Compound (D) in thereaction scheme 2 is a known one. A work-up method in the reactionscheme 2 for preparing Compound (FK) at a markedly high conversion rate(reaction efficiency) is however utterly unknown when Compound (EM)obtained by the above reaction, particularly when it is an unpurifiedcompound, is subjected to the oxidation reaction (in the above reactionscheme 1) in the next step.

Compound (EM) can be prepared, for example, by using Compound (D),adding thereto 1-aminopropan-2-ol, and reacting the resulting mixture ata temperature of from about −80° C. to 50° C. in an organic solvent (forexample, tetrahydrofuran (THF), diethyl ether, tert-butyl methyl ether(t-BuOMe), dioxane, hexamethylphosphoric acid triamide (HMPA),acetonitrile, toluene, ethylbenzene, diglyme, heptane, hexane, orcyclohexane, or a solvent obtained by mixing the above-mentioned organicsolvents as needed), in the presence of a base (for example, lithiumdiisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiN(TMS)₂),sodium bis(trimethylsilyl)amide (NaN(TMS)₂), potassiumbis(trimethylsilyl)amide (KN(TMS)₂), n-butyl lithium, sec-butyl lithium,or tert-butyl lithium, or a base obtained by mixing the above-mentionedbases as needed), in the presence or absence of an inorganic salt (forexample, lithium chloride, lithium bromide, zinc chloride, or palladiumdiacetate (Pd(OAc)₂), or an inorganic salt obtained by mixing theabove-mentioned inorganic salts as needed), in the presence of anactivating reagent (for example, trifluoromethanesulfonic anhydride((CF₃SO₂)₂O), diethyl chlorophosphate ((EtO)₂P(O)Cl), trichlorosilane(TMSCl), phosphoryl chloride (P(O)Cl₃), or bismorpholinophosphorylchloridate (BMPC):

or a reagent obtained by mixing the above-mentioned activating reagentsas needed).

The work-up method to be conducted after the reaction for preparingCompound (EM) from Compound (D) in the reaction scheme 2 can bepositioned as one of the characteristics of the present invention. Thework-up method is preferably conducted in a water soluble solution neara pH range from weakly acidic to weakly alkaline (from about pH 3.5 toabout pH 10.5). The water soluble solution is more preferably near a pHrange from weakly acidic to weakly alkaline (from about pH 4.5 to about9.0), particularly preferably near a pH range from weakly acidic toneutral (from about pH 5.5 to about 8.0). Such a work-up method can beclassified roughly into two methods: that is, a method including a stepof quenching with an ammonium ion-containing solution and a methodincluding a step of quenching with an ammonium ion-free solution.

The method including a step of quenching with an ammonium ion-containingsolution can be conducted by adding an aqueous solution of ammoniumchloride in a reaction vessel in which the reaction for preparingCompound (EM) from Compound (D) has been conducted by theabove-mentioned process to quench and then conducting sufficient waterwashing of the organic layer obtained by a separation operation. It canalso be conducted by adding, to an aqueous solution of ammoniumchloride, the reaction mixture obtained by the reaction for preparingCompound (EM) from Compound (D), to quench and then subjecting theresulting mixture to sufficient water washing.

The term “sufficient water washing” as used herein means continuingwater washing until the remaining content of an ammonium ion in theorganic layer decreases to at least about 170 ppm or less, preferablyabout 111 ppm or less, more preferably about 91 ppm or less, still morepreferably about 72 ppm or less, still more preferably about 53 ppm orless, particularly preferably about 33 ppm or less, relative to Compound(EM); continuing water washing until the molar ratio of an ammonium ionin the organic layer decreases to at least about 145% or less,preferably about 94% or less, more preferably about 78% or less, morepreferably about 61% or less, still more preferably 45% or less,particularly preferably about 28% or less, relative to an oxidationcatalyst used for the oxidation reaction of Compound (EM); or continuingwater washing until both of the above-mentioned conditions aresatisfied.

The method including a step of quenching with an ammonium ion-freesolution can be conducted by adding, to a reaction vessel in which thereaction for preparing Compound (EM) from Compound (D) has beenconducted, an aqueous solution of sodium dihydrogen phosphate, anaqueous solution of sodium monohydrogen phosphate, a phosphate buffer, apotassium phosphate buffer, a phosphate buffer saline, an acetate buffer(acetic acid+sodium acetate), a citrate buffer (citric acid+sodiumcitrate), a citrate-phosphate buffer, a borate buffer, or a tartratebuffer to quench and then conducting water washing of the organic layerobtained by a separation operation. It can also be conducted by addingthe reaction mixture obtained by the reaction for preparing Compound(EM) from Compound (D) to an aqueous solution of sodium dihydrogenphosphate, an aqueous solution of sodium monohydrogen phosphate, aphosphate buffer, a potassium phosphate buffer, a phosphate buffersaline, an acetate buffer (acetic acid+sodium acetate), a citrate buffer(citric acid+sodium citrate), a citrate-phosphate buffer, a boratebuffer, or a tartrate buffer to quench and then conducting water washingof the organic layer as described above. Different from the waterwashing conducted when the above-mentioned aqueous solution of ammoniumchloride is used, no particular limitation is imposed on the waterwashing in this operation and water washing at only once is sufficient.The solution to be used in such a step of quenching with an ammoniumion-free solution is preferably an aqueous solution of sodium dihydrogenphosphate, an aqueous solution of sodium monohydrogen phosphate, and/ora phosphate buffer, more preferably an aqueous solution of sodiumdihydrogen phosphate and/or a phosphate buffer, particularly preferablya phosphate buffer.

By conducting the work-up so as to create, in the reaction system of asubsequent oxidation reaction, a circumstance containing an ammonium ionas less as possible, the oxidation reaction from Compound (EM) toCompound (FK) can be conducted at a markedly high conversion rate(reaction efficiency) with good reproducibility.

In the present invention, from the unpurified compound (EM) obtained bythe above-mentioned work-up method, Compound (FK) can be prepared evenwithout conducting purification such as distillation, silica gelchromatography, or recrystallization as described above, because theoxidation reaction proceeds at a markedly high conversion rate (reactionefficiency) with good reproducibility.

In the present invention, Compound (E) obtained by using(R)-1-aminopropan-2-ol or Compound (E′) obtained by using(S)-1-aminopropan-2-ol can be obtained in a manner similar to that ofthe above-mentioned reaction scheme 2, instead of Compound (EM) obtainedby using 1-aminopropan-2-ol in the reaction scheme 2.

[Use for Pharmaceuticals]

Compound (FK) in the present invention is an important synthesisintermediate of Compound (P) having sedative and anesthetic actions.Compound (P) is useful as a sedative or an anesthetic.

This application claims priority to Japanese Patent Application No.2013-041492 filed on Mar. 4, 2013, the entire contents of which areincorporated by reference herein.

In this specification, all the contents of the patent documents,non-patent documents, and reference documents explicitly cited hereincan be cited as a part of the specification.

EXAMPLES

The present invention will hereinafter be described by Examples, but itis not limited to or by them.

The solvent in parentheses shown in the description of separation bychromatography or TLC is an eluting solvent or developing solvent usedtherefor and a ratio means a ratio by volume.

The solvent in parentheses shown in the description of NMR is a solventused in measurement.

The compound name used herein is named using ACD/Name (trade mark) whichis a computer program for naming generally based on the IUPAC rules ornamed according to IUPAC nomenclature.

Example 1 Reaction from3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester (Compound (D)) to3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (Compound (EM))

To Compound (D) (1.0 mmol) in 1.0 mL of tetrahydrofuran was addedbismorpholinophosphoryl chloridate (BMPC) (1.2 mmol). At 0° C. or less,a tetrahydrofuran solution (1.8 M, 1.0 mmol, 0.56 mL) of lithiumdiisopropylamide was added dropwise to the reaction mixture. At 0° C., asolution of 1-aminopropan-2-ol (1.3 mmol) in 0.4 mL of tetrahydrofuranwas added dropwise to the reaction mixture. The resulting reactionmixture was stirred overnight at 0° C.

Example 2 Work-Up Method in Synthesis of Compound (EM) Example 2-1Work-Up Method with Aqueous Solution of Ammonium Chloride

To the reaction mixture of Example 1 were added about 16 mL of t-butylmethyl ether and about 10 mL of an aqueous solution of ammonium chloride(concentration: 25%) to separate it into layers. The organic layer thusobtained was washed with about 10 mL of an aqueous solution of ammoniumchloride and then washed with water so as to decrease the weight ratioof an ammonium ion content in the organic layer to 170 ppm or lessrelative to Compound (EM). The organic layer thus obtained wasconcentrated to about 1.0 mL under reduced pressure. Toluene was addedto the organic layer, followed by concentration under reduced pressureto about 1.0 mL. The toluene solution thus obtained was cooled to 0° C.The solid thus precipitated was collected by filtration and then driedto obtain Compound (EM) having the following physical properties. Themeasurement procedure of an ammonium ion content will be describedlater.

TLC: Rf 0.35 (ethyl acetate);

¹H-NMR (CDCl₃): δ 8.70-8.60 (m, 1H), 7.88-7.82 (m, 1H), 7.81-7.75 (m,1H), 7.53-7.47 (m, 1H), 7.40-7.33 (m, 2H), 7.15-7.10 (m, 1H), 5.71-5.65(m, 1H), 5.20-4.70 (m, 1H), 4.15-3.95 (m, 1H), 3.71 (s, 3H), 3.48-3.38(m, 1H), 3.33-3.14 (m, 1H), 3.30-3.20 (m, 1H), 2.85-2.73 (m, 1H),2.66-2.35 (m, 3H), 1.20-1.18 (m, 3H).

HPLC conditions

Column: YMC-Pack ODS-AQ (length: 25 cm, inner diameter: 4.6 mm, particlesize: 3 μm, YMC)

Column temperature: 25° C.

Mobile phase: 10 mM aqueous potassium dihydrogen phosphatesolution/acetonitrile=55/45

Flow rate: 0.7 mL/min

Detector: UV 230 nm

Injection amount: 5 μL

Analysis time: 40 minutes

The retention time under the above-mentioned conditions is 12.3 minutesand 12.8 minutes.

Example 2-2 Work-Up Method with Sodium Dihydrogen Phosphate and/orPhosphate Buffer

To the reaction mixture of Example 1 were added about 16 mL of t-butylmethyl ether and about 16 mL of an aqueous solution of sodium dihydrogenphosphate (concentration: 20%) to separate it into layers. The organiclayer thus obtained was washed with about 10 mL of a phosphate bufferand then washed twice with water (about 5 mL). The organic layer thusobtained was concentrated to about 1.0 mL under reduced pressure.Toluene was added to the organic layer and the resulting mixture wasconcentrated to about 1.0 mL under reduced pressure. The toluenesolution thus obtained was cooled to 0° C. The solid thus precipitatedwas collected by filtration and then dried to obtain Compound (EM)having the following physical properties.

TLC: Rf 0.35 (ethyl acetate)

¹H-NMR (CDCl₃): δ 8.70-8.60 (m, 1H), 7.88-7.82 (m, 1H), 7.81-7.75 (m,1H), 7.53-7.47 (m, 1H), 7.40-7.33 (m, 2H), 7.15-7.10 (m, 1H), 5.71-5.65(m, 1H), 5.20-4.70 (m, 1H), 4.15-3.95 (m, 1H), 3.71 (s, 3H), 3.48-3.38(m, 1H), 3.33-3.14 (m, 1H), 3.30-3.20 (m, 1H), 2.85-2.73 (m, 1H),2.66-2.35 (m, 3H), 1.20-1.18 (m, 3H).

HPLC conditions

Column: YMC-Pack ODS-AQ (length: 25 cm, inner diameter: 4.6 mm, particlesize: 3 μm, YMC)

Column temperature: 25° C.

Mobile phase: 10 mM aqueous potassium dihydrogen phosphatesolution/acetonitrile=55/45

Flow rate: 0.7 mL/min

Detector: UV 230 nm

Injection amount: 5 μL

Analysis time: 40 minutes

The retention time under the above-mentioned conditions is 12.3 minutesand 12.8 minutes.

Example 3 Preparation of3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester (Compound (FK)) from3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (Compound (EM))

Example 3-1 Oxidation Reaction Using AZADO as Oxidation Catalyst

To the unpurified compound (EM) (1.0 mmol) obtained in Example 1 andExample 2 in a mixed solvent of 3.4 mL of methyl acetate and 5.7 mL oftoluene were added 0.46 mg of AZADO (0.003 mol), 1.9 mL of an aqueoussolution of sodium hydrogen carbonate (7.7 wt %), and 6.0 mg ofpotassium bromide (0.05 mmol). At 0° C., 640 mg of an aqueous solutionof sodium hypochlorite (14 wt %; 1.2 mmol) was added to the reactionmixture. The resulting mixture was stirred at 0° C. for one hour,followed by HPLC to find a conversion rate and confirm disappearance ofthe raw material. To the reaction mixture was added an aqueous solutionof sodium thiosulfate to separate it into layers. The organic layer thusobtained was washed with an aqueous solution of ammonium chloride. Theresulting organic layer was concentrated under reduced pressure. To theresidue thus obtained were added toluene and methanol, followed byazeotropy to obtain Compound (FK) having the following physicalproperties.

TLC: Rf 0.45 (ethyl acetate);

HPLC conditions

Column: YMC-Pack ODS-AQ (length: 25 cm, inner diameter: 4.6 mm, particlesize: 3 μm, YMC)

Column temperature: 25° C.

Mobile phase: 10 mM aqueous potassium dihydrogen phosphatesolution/acetonitrile=55/45

Flow rate: 0.7 mL/min

Detector: UV 230 nm

Injection amount: 5 μL

Analysis time: 40 minutes

The retention time under the above-mentioned conditions is 16.9 minutes.

Example 3-2 Oxidation Reaction Using AZADOH as Oxidation Catalyst

By an operation similar to that of Example 3-1 except for the use of0.46 mg of AZADOH (0.003 mmol) instead of AZADO, Compound (FK) havingthe following physical properties was obtained.

TLC: Rf 0.45 (ethyl acetate);

HPLC conditions

Column: YMC-Pack ODS-AQ (length: 25 cm, inner diameter: 4.6 mm, particlesize: 3 μm, YMC)

Column temperature: 25° C.

Mobile phase: 10 mM aqueous potassium dihydrogen phosphatesolution/acetonitrile=55/45

Flow rate: 0.7 mL/min

Detector: UV 230 nm

Injection amount: 5 μL

Analysis time: 40 minutes

The retention time under the above-mentioned conditions is 16.9 minutes.

Example 4 Synthesis of3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester (“Compound (E)”)

By operations similar to those of Example 1 and Example 2 except for theuse of (R)-1-aminopropan-2-ol instead of 1-aminopropan-2-ol, Compound(E) having the following physical properties was obtained.

TLC: Rf 0.35 (ethyl acetate);

¹H-NMR (CDCl₃): δ 8.66 (ddd, J=4.9, 1.7, 0.9 Hz, 1H), 7.85 (d, J=7.6 Hz,1H), 7.78 (td, J=7.6, 1.6 Hz, 1H), 7.50 (dd, J=8.8, 2.4 Hz, 1H), 7.38(d, J=2.4 Hz, 1H), 7.40-7.33 (m, 1H), 7.12 (d, J=8.8 Hz, 1H), 5.69 (t,J=5.4 Hz, 1H), 5.17 (s, 1H), 4.06-3.93 (m, 1H), 3.71 (s, 3H), 3.48-3.38(m, 1H), 3.33 (dd, J=10.0, 4.0 Hz, 1H), 3.26 (ddd, J=14.2, 6.4, 2.0 Hz,1H), 2.85-2.73 (m, 1H), 2.66-2.35 (m, 3H), 1.17 (d, J=6.4 Hz, 3H).

HPLC conditions

Column: YMC-Pack ODS-AQ (length: 25 cm, inner diameter: 4.6 mm, particlesize: 3 μm, YMC)

Column temperature: 25° C.

Mobile phase: 10 mM aqueous potassium dihydrogen phosphatesolution/acetonitrile=55/45

Flow rate: 0.7 mL/min

Detector: UV 230 nm

Injection amount: 5 μL

Analysis time: 40 minutes

The retention time under the above-mentioned conditions is 12.8 minutes.

Example 5 Preparation of Compound (FK) from Compound (E)

An operation similar to that of Example 3 (Example 3-1 or Example 3-2)was conducted using Compound (E) prepared in Example 4 to obtainCompound (FK) having the following physical properties.

TLC: Rf 0.45 (ethyl acetate);

HPLC conditions

Column: YMC-Pack ODS-AQ (length: 25 cm, inner diameter: 4.6 mm, particlesize: 3 μm, YMC)

Column temperature: 25° C.

Mobile phase: 10 mM aqueous potassium dihydrogen phosphatesolution/acetonitrile=55/45

Flow rate: 0.7 mL/min

Detector: UV 230 nm

Injection amount: 5 μL

Analysis time: 40 minutes

The retention time under the above-mentioned conditions is 16.9 minutes.

Example 6 Preparation of Compound (P) from Compound (FK)

To Compound (FK) prepared in Example 3 were added 32 mg ofbenzenesulfonic acid and 0.46 mL of methanol. The resulting mixture wasstirred at 50° C. for five hours. After filtering the reaction mixture,110 mg of benzenesulfonic acid and 0.2 mL of methanol were added toobtain Compound (P)

TLC: Rf 0.42 (n-hexane/ethyl acetate=20/80)

¹H-NMR (CDCl₃): δ 16.0 (br s, 1H), 8.59 (d, J=4.2 Hz, 1H), 8.18 (d,J=8.4 Hz, 1H), 7.95-7.90 (m, 2H), 7.88-7.84 (m, 1H), 7.84 (dd, J=8.6,2.2 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.51-7.48 (m, 1H), 7.50 (d, J=8.6Hz, 1H), 7.45-7.41 (m, 1H), 7.39-7.35 (m, 3H), 4.41 (dd, J=9.9, 3.9 Hz,1H), 3.61 (s, 3H), 2.98-2.89 (m, 1H), 2.83-2.68 (m, 3H), 2.42 (s, 3H).

HPLC conditions

Column: Cadenza CD-18 (length: 15 cm, inner diameter: 4.6 mm, particlesize: 3 μm, Imtakt)

Column temperature: 40° C.

Mobile phase: A: 10 mM aqueous potassium dihydrogen phosphate solution,B: methanol

A/B=from 50/50 (0 min) to 30/70 (50 minutes)

Flow rate: 1.0 mL/min

Detector: UV 230 nm

Injection amount: 10 μL

Analysis time: 50 minutes

The retention time under the above-mentioned conditions is 20.7 minutes.

Next, methods of measuring an ammonium ion content and calculating aconversion rate will be described, respectively.

Test Method 1: Measurement of Ammonium Ion Content

Standard solutions i to iv were analyzed using the analysis method shownbelow in a) and calibration curves were made. Sample solutions wereanalyzed and ammonium ion contents in Compound (EM), Compound (E), andCompound (E′) were determined, respectively, from the calibrationcurves. A preparation process b) of the standard solutions and apreparation process c) of the sample solutions are as described below.

a) Ion Chromatograph Analysis Conditions

Column: TSK-GEL IC-Cation (50×4.6 mm i.d.)

Eluting solution: 2 mmol/L nitric acid

Injection amount: 100 μL

Flow rate: 1.2 mL/min

Oven: 30° C.

Polarity: -

Response: 1.0 second

b) Preparation of Standard Solutions

After 100 mg of ammonium chloride was weighed, purified water was addedthereto to make the whole volume 100 mL (standard solution i). After 1mL of the resulting standard solution i was weighed, a mixed solution ofmethanol and water was added thereto to make the whole volume 100 mL(standard solution ii). After 10 mL of the resulting standard solutionii was weighed, a mixed solution of methanol and water was added theretoto make the whole volume 100 mL (standard solution iii). After 10 mL ofthe resulting standard solution iii was weighed, a mixed solution ofmethanol and water was added thereto to make the whole volume 100 mL(standard solution iv).

c) Preparation of Sample Solutions

After 20 mg of each of Compound (EM), Compound (E), and Compound (E′)was weighed, a mixed solution of methanol and water was added thereto tomake the whole volume 20 ml. The resulting solution was used as a samplesolution.

Test Method 2: Calculation Method of Conversion Rate

$\begin{matrix}{{{Conversion}\mspace{14mu} {Rate}} = {\frac{A_{FK}}{A_{FK} + A_{({{EM},\mspace{14mu} E,\mspace{14mu} {{or}\mspace{14mu} E^{\prime}}})}} \times 100}} & \left\lbrack {{Equation}\mspace{14mu} 1} \right\rbrack\end{matrix}$

In the above equation, A represents a peak area of each compound in HPLCusing the below-described method;

A_(FK) represents a peak area of Compound (FK);

A_(EM) represents a peak area of Compound (EM);

A_(E) represents a peak area of Compound (E); and

A_(E′) represents a peak area of Compound (E′).

HPLC conditions

Column: YMC-Pack ODS-AQ (length: 25 cm, inner diameter: 4.6 mm, particlesize: 3 μm, YMC)

Column temperature: 25° C.

Mobile phase: 10 mM aqueous potassium dihydrogen phosphatesolution/acetonitrile=55/45

Flow rate: 0.7 mL/min

Detector: UV 230 nm

Injection amount: 5 μL

Analysis time: 40 minutes

Example 7 Study on Reproducibility of Conversion Rate (ReactionEfficiency)

The following experiment has revealed by using, for example, Compound(E) the reason why a reaction for preparing Compound (FK) from theunpurified Compound (EM), Compound (E), or Compound (E′) does notachieve a conversion rate (reaction efficiency) with reproducibility.

Experiment of Cause Investigation 1 Addition of Expected Impurity intoCompound (E)

Experiment of Cause Investigation 1-1 Addition of Ammonium Chloride

Ammonium chloride (2.0 mg, 0.038 mmol, weight ratio relative to Compound(E): 2000 ppm) was added to Compound (E) in a mixed solvent of 7.5 mL ofmethyl acetate, 12.5 mL of toluene, and 0.1 mL of water. At 0° C., 13 mgof potassium bromide (0.11 mmol), an aqueous solution of sodium hydrogencarbonate (4 mL, 7.7 wt %), and 0.99 mg of AZADO (0.0065 mmol) wereadded to the reaction mixture. At 0° C., 1.6 g of an aqueous solution ofsodium hypochlorite (2.6 mmol, 12.3 wt %) was added to the reactionmixture. After stirring for one hour, a conversion rate of the reactionmixture was determined by the above-mentioned test method 2.

Experiment of Cause Investigation 1-2 Addition of (R)-1-Aminopropan-2-Ol

An operation similar to that of Experiment of cause investigation 1-1except that ammonium chloride (2.0 mg) was replaced by the same weightof (R)-1-aminopropan-2-ol (2.0 mg) was conducted and a conversion ratewas determined using the above-mentioned test method 2.

Experiment of Cause Investigation 1-3 No Addition

An operation similar to that of Experiment of cause investigation 1-1was conducted without adding ammonium chloride instead of addingammonium chloride (2.0 mg) and a conversion rate was determined usingthe above-mentioned test method 2.

The results of the experiment of cause investigation 1 are shown belowin Table 1. It has been found from Table 1 that when no ammoniumchloride was added (Experiment of cause investigation 1-3) and when(R)-1-aminopropan-2-ol was added (Experiment of cause investigation1-2), the oxidation reaction proceeded without a problem, a conversionrate was as high as 99.9%, and the reaction efficiency was good. Whenammonium chloride was added (Experiment of cause investigation 1-1), onthe other hand, the conversion rate of the oxidation reaction was 78.5%and the reaction efficiency was not quite satisfactory.

TABLE 1 Experiment Conversion of cause rate of oxidation investigation 1Addition or no addition of impurity reaction 1-1 Addition of ammoniumchloride 78.5% 1-2 Addition of (R)-1-aminopropan-2-ol 99.9% 1-3 Noaddition 99.9%

Experiment of Cause Investigation 2 Addition of Ammonium Chloride Analoginto Compound (E)

Experiment of Cause Investigation 2-1 Addition of Ammonium Chloride

Ammonium chloride (2.0 mg, 0.038 mmol) was added to Compound (E) (1.0 g,2.2 mmol) in a mixed solvent of 7.5 mL of methyl acetate, 12.5 mL oftoluene, and 0.1 mL of water. At 0° C., 13 mg of potassium bromide (0.11mmol), an aqueous solution of sodium hydrogen carbonate (4 mL, 7.7 wt%), and 0.99 mg of AZADO (0.0065 mmol) were added to the reactionmixture. At 0° C., 1.6 g of an aqueous solution of sodium hypochlorite(2.6 mmol, 12.3 wt %) was added to the reaction mixture. After stirringfor one hour, a conversion rate of the reaction mixture was determinedusing the above-mentioned test method 2.

Experiment of Cause Investigation 2-2 Addition of Ammonium Bromide

An operation similar to that of Experiment of cause investigation 2-1except that ammonium chloride (0.038 mmol) was replaced by the samemolar amount of ammonium bromide (3.7 mg, 0.038 mmol) was conducted anda conversion rate was determined using the above-mentioned test method2.

Experiment of Cause Investigation 2-3 Addition of Ammonium Acetate

An operation similar to that of Experiment of cause investigation 2-1except that ammonium chloride (0.038 mmol) was replaced by the samemolar amount of ammonium acetate (2.9 mg, 0.038 mmol) was conducted anda conversion rate was determined using the above-mentioned test method2.

Experiment of Cause Investigation 2-4 Addition of Ammonium Carbonate

An operation similar to that of Experiment of cause investigation 2-1except that ammonium chloride (0.038 mmol) was replaced with the samemolar amount of ammonium carbonate (3.6 mg, 0.038 mmol) was conductedand a conversion rate was determined using the above-mentioned testmethod 2.

Experiment of Cause Investigation 2-5 Addition of Aqueous AmmoniaSolution

An operation similar to that of Experiment of cause investigation 2-1except that ammonium chloride (0.038 mmol) was replaced by the samemolar amount of a 28 wt % aqueous ammonia solution (2.3 mL, 0.038 mmol)was conducted and a conversion rate was determined using theabove-mentioned test method 2.

Experiment of Cause Investigation 2-6 Addition of Sodium Chloride

An operation similar to that of Experiment of cause investigation 2-1except that ammonium chloride (0.038 mmol) was replaced by the samemolar amount of sodium chloride (2.2 mg, 0.038 mmol) was conducted and aconversion rate was determined using the above-mentioned test method 2.

Experiment of Cause Investigation 2-7 Addition of Hydrochloric Acid

An operation similar to that of Experiment of cause investigation 2-1except that ammonium chloride (0.038 mmol) was replaced by the samemolar amount of 6 mol/L hydrochloric acid (0.0063 mL, 0.038 mmol) wasconducted and a conversion rate was determined using the above-mentionedtest method 2.

Experiment of Cause Investigation 2-8 Addition of TetrabutylammoniumBromide

An operation similar to that of Experiment of cause investigation 2-1except that ammonium chloride (0.038 mmol) was replaced by the samemolar amount of tetrabutylammonium bromide (12.1 mg, 0.038 mmol) wasconducted and a conversion rate was determined using the above-mentionedtest method 2.

The results of the experiment of cause investigation 2 are shown belowin Table 2. It has been found from Table 2 that in Experiments of causeinvestigation 2-6 and 2-7, the oxidation reaction proceeded without aproblem, the conversion rate was as high as about 99% or more, and thereaction efficiency was good, suggesting that the chloride ion ofammonium chloride is not a substance impeding the oxidation reaction. InExperiments of cause investigation 2-2,2-3,2-4, and 2-5, on the otherhand, the conversion rate of the oxidation reaction was from about 30 to60% and the reaction efficiency was much inferior, suggesting that theammonium ion of ammonium chloride was presumed to be a substanceimpeding the oxidation reaction. In Experiment of cause investigation2-8 in which a tetrabutylammonium ion, that is, the same cation as theammonium ion was added, the oxidation reaction proceeded without aproblem. From these findings, a substance impeding the efficientprogress of the oxidation reaction was strongly presumed to be anammonium ion.

TABLE 2 Experiment of cause Addition of ammonium chloride Conversionrate of investigation 2 analog oxidation reaction 2-1 Ammonium chloride78.5% 2-2 Ammonium bromide 37.3% 2-3 Ammonium acetate 29.9% 2-4 Ammoniumcarbonate 59.8% 2-5 Aqueous ammonia solution 55.8% 2-6 Sodium chloride99.9% 2-7 Hydrochloric acid 98.9% 2-8 Tetrabutylammonium bromide 98.2%

Based on the above-mentioned results of Experiments of causeinvestigation 1 and 2, Experiment 3 was conducted to find a correlationbetween an ammonium ion content and a conversion rate from Compound (E)to Compound (FK).

Experiment 3 Experiment on Correlation Between Ammonium Ion Content andConversion Rate

Compound (FK) was prepared by an operation similar to that of Example 3by using Compound (E) different in lot whose ammonium content had beendetermined using the above-mentioned test method 1, a conversion ratewas calculated using the test method 2, and a correlation between anammonium ion content and a conversion rate was found. The ammonium ioncontent and a conversion rate of each lot are as shown below in Table 3.Incidentally, for example, an ammonium ion content of 20 ppm in theExperiment 3-1 means that an ammonium ion content is 20 μg relative to 1g of Compound (E).

TABLE 3 Experiment 3 Ammonium ion Conversion rate of oxidation (Lot No.)content (ppm) reaction (%) 3-1 20 100 3-2 74 98.4 3-3 130 99.0 3-4 16398.0 3-5 211 94.5 3-6 221 94.3 3-7 243 92.6 3-8 272 95.7

It has been found from the above results that when Compound (E) havingan ammonium ion content of about 200 ppm or more is used as a rawmaterial of an oxidation reaction, a conversion rate of the oxidationreaction varies and the oxidation reaction is not stable. It has alsobeen found that when Compound (E) having an ammonium ion content ofabout 170 ppm or less is used as a raw material of an oxidationreaction, on the other hand, a conversion rate of the oxidation reactionis 98% or more and the oxidation reaction is stable with goodreproducibility.

FIG. 1 shows these results as a graph.

FIG. 2 shows both the results of FIG. 1 and an approximate curve (linearapproximation). Although a negative relation can be found between anammonium ion content and a conversion rate from Compound (E) to Compound(FK), it is preferred to understand that the approximate curve (linearapproximation) shown in this graph is only one example because there arevarious ways how to find an approximate curve. The following was theequation of the approximate curve in the graph: [conversion rate(%)=−0.0258×(NH₄ ⁺ content (ppm)+100.87)].

INDUSTRIAL APPLICABILITY

According to the present invention, Compound (FK) can be prepared at amarkedly high conversion rate and/or oxidation catalyst efficiency withgood reproducibility from a compound selected from the group consistingof Compound (EM), Compound (E), and Compound (E′), even if it is anunpurified compound. Compound (FK) is an important synthesisintermediate of Compound (P) having sedative and anesthetic actions.Since the preparation process of the present invention can stably supplyCompound (FK) with good reproducibility without conducting a particularpurification step, it is very useful from the standpoint of industrialproductivity of Compound (P) which is an active pharmaceuticalingredient.

1. A process for preparing3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester by subjecting, to an oxidation reaction, a compoundselected from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester in the presence of at least one oxidation catalystselected from the group consisting of a compound represented by thefollowing formula (I-1), (I-2) or (I-3):

(wherein, R₁, R₂, and R₅ each independently represent a hydrogen atom, ahalogen, a hydroxyl group, a C₁₋₃ alkyl group, or a C₁₋₃ alkoxy group,R₃ represents a hydrogen atom or a halogen, and

represents N—O^(•), N—OH, or N⁺═O), 2,2,6,6-tetramethylpiperidin-N-oxyl,2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxyl, and2,2,6,6-tetramethyl-1,4-piperidinediol, salts thereof, and solvatesthereof, wherein the oxidation reaction is conducted in a reactionsystem satisfying at least one of the following conditions (a) to (c):(a) in the absence of an ammonium ion, (b) in the presence of anammonium ion in a weight ratio of 170 ppm or less relative to thecompound selected, as the compound to be subjected to the oxidationreaction, from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and (c) in the presence of an ammonium ion in a molarratio of 145% or less relative to the oxidation catalyst.
 2. Thepreparation process according to claim 1, wherein the compound selectedfrom the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(5)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester is an unpurified compound.
 3. The preparationaccording to claim 1, wherein the oxidation reaction is conducted at aconversion rate of 98% or more.
 4. The preparation process according toclaim 1, wherein3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester is obtained by conducting an addition reaction between3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester and 1-aminopropan-2-ol, followed by washing with awater soluble solution having a pH of from about 3.5 to about 10.5. 5.The preparation process according to claim 1, wherein3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester is obtained by conducting an addition reaction between3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester and (R)-1-aminopropan-2-ol, followed by washing with awater soluble solution having a pH of from about 3.5 to about 10.5. 6.The preparation process according to claim 1, wherein3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester is obtained by conducting an addition reaction between3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester and (S)-1-aminopropan-2-ol, followed by washing with awater soluble solution having a pH of from about 3.5 to about 10.5. 7.(canceled)
 8. The preparation process according to claim 4, wherein thewater soluble solution is an aqueous solution of ammonium chloride, anaqueous solution of sodium monohydrogen phosphate, an aqueous solutionof sodium dihydrogen phosphate, and/or a phosphate buffer.
 9. Thepreparation process according to claim 1, wherein the oxidation catalystis either 2-azaadamantane-N-oxyl or 2-azaadamantan-2-ol.
 10. A processfor preparing3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester, comprising subjecting3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester to an oxidation reaction in the presence of2-azaadamantane-N-oxyl or 2-azaadamantan-2-ol as an oxidation catalyst,wherein the3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester is a compound obtained by conducting an additionreaction between3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester and (R)-1-aminopropan-2-ol, followed by washing with aphosphate buffer.
 11. The preparation process according to claim 10,wherein3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester is an unpurifiedcompound. 12.3-[(S)-7-Bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester, obtained by subjecting a compound selected from thegroup consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(5)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester to an oxidation reaction in the presence of at leastone oxidation catalyst selected from the group consisting of a compoundrepresented by the following formula (I-1), (I-2) or (I-3):

(wherein, all the symbols have the same meanings as claimed in claim 1),2,2,6,6-tetramethylpiperidin-N-oxyl, 2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxyl, and2,2,6,6-tetramethyl-1,4-piperidinediol, salts thereof, and solvatesthereof, wherein the oxidation reaction is conducted in a reactionsystem satisfying at least one of the following conditions (a) to (c):(a) in the absence of an ammonium ion, (b) in the presence of anammonium ion in a weight ratio of 170 ppm or less relative to thecompound selected, as the compound to be subjected to the oxidationreaction, from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and (c) in the presence of an ammonium ion in a molarratio of 145% or less relative to the oxidation catalyst. 13.3-[(45)-8-Bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionicacid methyl ester benzenesulfonate, obtained by the following steps (i)to (iii): (i) a step of conducting an addition reaction between3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester and (R)-1-aminopropan-2-ol and then washing with aphosphate buffer to obtain3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester; (ii) a step of subjecting the3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester obtained in the step (i) to an oxidation reaction inthe presence of 2-azaadamantane-N-oxyl or 2-azaadamantan-2-ol as anoxidation catalyst to obtain3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester; and (iii) a step of reacting the3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester obtained in the step (ii) with benzenesulfonic acid toobtain3-[(45)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionicacid methyl ester benzenesulfonate.
 14. A reaction compositioncomprising a compound selected from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, an oxidizing agent, an oxidation catalyst, and asolvent, wherein the reaction composition contains no ammonium ion orcontains an ammonium ion in a weight ratio of 170 ppm or less relativeto the compound selected, as the compound to be subjected to theoxidation reaction, from the group consisting of3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester,3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester, and3-[(S)-7-bromo-2-((S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester or in a molar ratio of 145% or less relative to theoxidation catalyst.
 15. The reaction composition according to claim 14,for the preparation of3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionicacid methyl ester.
 16. The reaction composition according to claim 14 or15, wherein the oxidation catalyst is selected from the group consistingof a compound represented by the following formula (I-1), (I-2) or(I-3):

(wherein, all the symbols have the same meanings as claimed in claim 1),2,2,6,6-tetramethylpiperidin-N-oxyl, 2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxyl, and2,2,6,6-tetramethyl-1,4-piperidinediol, salts thereof, and solvatesthereof.
 17. The preparation according to claim 2, wherein the oxidationreaction is conducted at a conversion rate of 98% or more.
 18. Thepreparation process according to claim 5, wherein the water solublesolution is an aqueous solution of ammonium chloride, an aqueoussolution of sodium monohydrogen phosphate, an aqueous solution of sodiumdihydrogen phosphate, and/or a phosphate buffer.
 19. The preparationprocess according to claim 6, wherein the water soluble solution is anaqueous solution of ammonium chloride, an aqueous solution of sodiummonohydrogen phosphate, an aqueous solution of sodium dihydrogenphosphate, and/or a phosphate buffer.
 20. The reaction compositionaccording to claim 15, wherein the oxidation catalyst is selected fromthe group consisting of a compound represented by the following formula(I-1), (I-2) or (I-3):

(wherein, all the symbols have the same meanings as claimed in claim 1),2,2,6,6-tetramethylpiperidin-N-oxyl, 2,2,6,6-tetramethylpiperidin-1-ol,4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxyl, and2,2,6,6-tetramethyl-1,4-piperidinediol, salts thereof, and solvatesthereof.
 21. The preparation process according to claim 1, wherein3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionicacid methyl ester is obtained by conducting an addition reaction between3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionicacid methyl ester and 1-aminopropan-2-ol, followed by washing.